EGR-1 was cloned in several laboratories nearly simultaneously (1-6) as the result of efforts to define new factors responsible for growth regulation. However, direct evidence for growth promoting role by EGR-1 remained elusive. Our studies with PDGF-B transformed NIH-3T3 and human HT1080 fibrosarcoma cells (7-8) and studies of others with v-raf transformed NIH-3T3 cells (9) have revealed that EGR-1 actually exerts a strong growth and transformation suppressor activity including decreased tumorigenicity (7-8). Conversely, expression of antisense EGR-1 RNA in NIH-3T3 cells (7) and human prostate carcinoma PC3 cells (8) leads to reduced endogenous EGR-1 and a much more transformed phenotype indicating that endogenous EGR-1 is growth suppressive. Numerous studies show that EGR-1 is within a small region of 5q31.1 that is consistently deleted in AML and other solid tumor malignancies (11-12, 41-43). Moreover, we find that EGR-1 is not expressed and/or uninducible in a variety of established and primary human tumor lines. Studies summarized here provide a mechanistic basis for the inhibition of transformation by EGR-1 by showing that EGR-1 activates a minimal human TGF-beta 1 promoter and causes secretion of active TGF- beta 1. It is hypothesized that suppression of transformation by EGR-1 is dependent on direct stimulation of the TGF- beta 1 gene leading to secretion of TGF- beta 1 which is growth suppressive for certain tumor cell lines. We will test whether the EGR-1/TGF-beta 1 is a general growth regulatory mechanism (AIM 1), whether EGR-1 is a physiologically relevant activator of TGF- beta 1 (AIM 2), whether induction of TGF-beta 1 by EGR-1 is due to direct TGF- beta 1 promoter binding by EGR-1 (AIM 3), whether restoration of TGF- beta 1 sensitivity in human colon and breast carcinomas also restores suppression by EGR-1 and whether TGF- beta 1 is essential for suppression of growth by EGR-1 (AIM 4), and whether loss of heterozygosity, other deletion or aberrant trans- regulation occur in the tumor lines which exhibit aberrant expression and regulation (AIM 5). These studies will elaborate a new mechanism of action for the transcription factor EGR-1 and will evaluate a new regulatory pathway controlling the expression of TGF- beta 1. Inactivation of the signal transduction pathway of TGF- beta 1 has been implicated as common in several major human malignancies and restoration TGF- beta 1 sensitivity suppresses transformation. Loss or defects in EGR-1 is a potential means of disrupting growth control by TGF- beta 1 and this is the tested here (AIM 2).